Raf kinase inhibitor protein negatively regulates FcεRI-mediated mast cell activation and allergic response

Abstract

The signaling cascades triggered by the cross-linkage of immunoglobulin E (IgE) with its high-affinity receptor (FcεRI) on mast cells contribute to multiple allergic disorders, such as asthma, rhinitis, and atopic dermatitis. Restraint of intracellular signals for mast cell activation is essential to restore homeostasis. In this study, we found that Raf kinase inhibitor protein (RKIP) negatively regulated mast cell activation. RKIP-deficient mast cells showed greater IgE−FcεRI-mediated activation than wild-type mast cells. Consistently, RKIP deficiency in mast cells rendered mice more sensitive to IgE−FcεRI-mediated allergic responses and ovalbumin-induced airway inflammation. Mechanistically, RKIP interacts with the p85 subunit of PI3K, prevents it from binding to GRB2-associated binding protein 2 (Gab2), and eventually inhibits the activation of the PI3K/Akt/NF-κB complex and its downstream signaling. Furthermore, the expression of RKIP was significantly down-regulated in the peripheral blood of asthma patients and in the IgE−FcεRI-stimulated mast cells. Collectively, our findings not only suggest that RKIP plays an important role in controlling mast cell-mediated allergic responses but also provide insight into therapeutic targets for mast cell-related allergic diseases.

Glaucocalyxin A Attenuates Allergic Responses by Inhibiting Mast Cell Degranulation through p38MAPK/NrF2/HO-1 and HMGB1/TLR4/NF-κB Signaling Pathways

“…The activation of mast cells depends on the activation of Syk, which is regulated by the interaction of Fc ε RI with Lyn and Fyn [ 31 ]. Syk plays an important role in regulating the production of inflammatory cytokines in mast cells by stimulating downstream molecules such as Gab2 and PLC- γ 1 [ 2 ]. Activation of these signaling pathways leads to mast cell degranulation and the release of proinflammatory cytokines.…”

“…Mast cells induce allergic inflammation through the secretion of inflammatory mediators [ 1 ], and a variety of cell membrane receptors are expressed on their surface. Among them, the combination of IgE and Fc ε RI and the crosslinking of Fc ε RI and multivalent antigens cause degranulation of mast cells, which in turn leads to the release of a large number of inflammatory mediators, including secreted granules (containing histamine and proteases), cytokines (such as TNF- α and IL-13), growth factors, and chemokines [ 2 ], which potentiate inflammatory immune responses via the secretion of cytokines [ 3 ]. Nrf2 is an important transcription factor in the cap'n'collar family.…”

RKIP as an Inflammatory and Immune System Modulator: Implications in Cancer

“…It was described that RKIP-deficient mast cells showed greater activation than wild-type mast cells and, consistently, RKIP deficiency in mast cells rendered mice more sensitive to allergic responses and ovalbumin-induced airway inflammation. Mechanistically, RKIP interacts with PI3K, preventing it from binding to GRB2-associated binding protein 2 (Gab2), and eventually inhibiting the activation of the PI3K/AKT/NF-κB complex and its downstream signalling [57].…”

Targeting M2 Macrophages Alleviates Airway Inflammation and Remodeling in Asthmatic Mice via miR-378a-3p/GRB2 Pathway

“…CD206 activation mediated GRB2 recruitment to initiate phagocytosis signaling in human monocyte-derived macrophages ( Rajaram et al, 2017 ). Several studies have shown the important effects of GRB2 in eosinophils, mast cells and T cells in allergic diseases ( Ben Baruch-Morgenstern et al, 2014 ; Massoud et al, 2016 ; Lin et al, 2018 ). Xu et al reported that miR-378a-3p sensitized ovarian cancer cells to cisplatin through targeting MAPK1/GRB2 ( Xu et al, 2018 ).…”